The invention relates to pharmaceutical compositions of a drug in a semi-ordered state and a polymer that improves the stability of the drug and enhances the concentration of the drug in a use environment.
Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug. Increasing the bioavailability of low-solubility drugs has been the subject of much research. Increasing bioavailability depends on improving the concentration of dissolved drug in solution to improve absorption.
It is well known that for a low-solubility drug that is capable of existing in either the crystalline or amorphous form, the amorphous form may temporarily provide a greater aqueous concentration of drug relative to the equilibrium concentrations obtained by dissolution of the crystalline drug form in a use environment. Such amorphous forms may consist of the amorphous drug alone, a dispersion of the drug in a matrix material, or the drug adsorbed onto a substrate. It is believed that such amorphous forms of the drug may dissolve more rapidly than the crystalline form, often dissolving faster than the drug can precipitate or crystallize from solution. As a result, the amorphous form may temporarily provide a greater-than equilibrium concentration of drug.
While such amorphous forms may temporarily show enhanced concentration of the drug in a use environment, nevertheless the improved concentration is often short-lived. Typically, the initially enhanced drug concentration is only temporary and quickly returns to the lower equilibrium concentration.
One approach to increase the bioavailability of low-solubility drugs has involved forming amorphous dispersions of drugs with polymers. Examples of attempts to increase drug concentration by forming a dispersion of the drug with a polymer include Nakamichi et al., U.S. Pat. No. 5,456,923, and Curatolo et al., EP 0901786A2.
One problem with using the amorphous form of a drug is that the solid drug may not be physically stable in the amorphous form. Often the crystalline form of the drug has a lower free energy, and thus over time the amorphous drug will tend to crystallize. The rate of crystallization may be influenced by storage conditions, such as temperature and humidity, as well as the constituents of the composition.
Similarly, a solid amorphous dispersion of polymer and drug may in some cases be unstable, either due to instability of the dispersion or the drug itself. For example, the dispersion may be physically unstable, causing the amorphous drug to separate from the dispersion. Once the drug separates from the dispersion, it may then be susceptible to crystallizing. Alternatively, the drug in the amorphous dispersion may be chemically unstable. The drug may degrade over time at moderate temperature and humidity levels or the drug may react with other constituents of the dispersion, resulting in a decrease in potency and an increase in drug-related impurities.
Accordingly, what is still desired is a composition comprising a drug in a form that is physically and/or chemically stable under typical storage conditions, that may be formed via practical processing conditions, and that may enhance the dissolution and/or bioavailability of poorly soluble drugs. These needs and others that will become apparent to one of ordinary skill are met by the present invention, which is summarized and described in detail below.